Process for preparing triazolones

ABSTRACT

The present process provides a improved method for the preparation of alkylsulfanyl substituted triazoles 2 which are useful intermediates in a new process for the preparation of triazolones 20.

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a divisional application of U.S. Ser. No. 12/156,145filed May 30, 2008 which claims the benefit of priority to U.S. Ser. No.60/932,216 filed May 30, 2007 which is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of3-[3-(4-methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-ylmethyl)phenoxy]-5-difluoromethyl-benzonitrilederivatives according to formula 2. Compounds of formula 2 are usefulfor the preparation of triazolones according to formula 20 utilizingadditional steps disclosed herein. Triazolones of formula 20 are usefulinhibitors of HIV-1 reverse transcriptase and are useful for treatingAIDS and HIV-1 mediated syndromes. The invention further providescompounds of formula 4 which are useful reagents in the presentlydisclosed process.

BACKGROUND OF THE INVENTION

The human immunodeficiency virus HIV is the causative agent of acquiredimmunodeficiency syndrome (AIDS), a disease characterized by thedestruction of the immune system, particularly of the CD4+ T-cell, withattendant susceptibility to opportunistic infections. HIV infection isalso associated with a precursor AIDS-related complex (ARC), a syndromecharacterized by symptoms such as persistent generalizedlymphadenopathy, fever and weight loss.

Currently available chemotherapy targets two crucial viral enzymes: HIVprotease and HIV reverse transcriptase. (J. S. G. Montaner et al.,Biomed. & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton,Biomed. & Pharmacother. 1999 53 :73-86; E. De Clercq, Curr. Med. Chem.2001 8:1543-1572). Two general classes of RTI inhibitors have beenidentified: nucleoside reverse transcriptase inhibitors (NRTI) andnon-nucleoside reverse transcriptase inhibitors. Currently the CCRSco-receptor has emerged as a potential target for anti-HIV chemotherapy(D. Chantry, Expert Opin. Emerg. Drugs 2004 9(1):1-7; C. G. Barber,Curr. Opin. Invest. Drugs 2004 5(8):851-861; D. Schols, Curr. TopicsMed. Chem. 2004 4(9):883-893; N. A. Meanwell and J. F. Kadow, Curr.Opin. Drug Discov. Dev. 2003 6(4):451-461). Drugs targeted at newenzymatic targets have entered the market including integrase inhibitorstypified by Raltegravir (Merck) has been approved by the FDA andElvitegravir (Gilead Sciences and Japan Tobacco) is in phase II trials.The CCR5 antagonist maraviroc (SELZENTRY™, Pfizer) has also beenapproved by the FDA for anti-HIV-1 therapy.

NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitorswhich bind reversibly at a nonsubstrate-binding site on the HIV reversetranscriptase thereby altering the shape of the active site or blockingpolymerase activity (R. W. Buckheit, Jr., Expert Opin. Investig. Drugs2001 10(8)1423-1442; E. De Clercq, Antiviral Res. 1998 38:153-179; E. DeClercq, Current medicinal Chem. 2001 8(13):1543-1572; G. Moyle, Drugs2001 61 (1):19-26). Initially viewed as a promising class of compounds,in vitro and in vivo studies quickly revealed the NNRTIs presented a lowbarrier to the emergence of drug resistant HIV strains andclass-specific toxicity. Although over thirty structural classes ofNNRTIs have been identified in the laboratory, only three compounds havebeen approved for HIV therapy: efavirenz, nevirapine and delavirdine.There remains a need for safer drugs with activity against wild type andcommonly occurring resistant strains of HIV.

5-Aralkyl-2,4-dihydro-[1,2,4]triazol-3-ones are non-nucleoside reversetranscriptase inhibitors have been disclosed by J. P. Dunn et al. inU.S. Pat. No. 7,208,509 granted Apr. 24, 2007 and by J. P. Dunn et al.in U.S. Publication No. 20060025462 filed Jun. 27, 2005. Pyridazinonenon-nucleoside reverse transcriptase inhibitors have been disclosed byJ. P. Dunn et al. in U.S. Pat. No. 7,208,509 granted Mar. 13, 2007 andU.S. Publication No. 20050215554 published Sep. 28, 2005. A process forthe preparation of pyridazinone non-nucleoside reverse transcriptaseinhibitors was disclosed by D. J. Kertesz in U.S. Patent Publication20050234236 published Oct. 20, 2005.

SUMMARY OF THE INVENTION

The current invention affords an improved process for the synthesis of3-[3-(1,4-dimethyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-2-fluoro-phenoxy]-5-difluoromethylbenzonitrilederivatives which are inhibitors of HIV-1 reverse transcriptase and areuseful in the treatment of HIV-1 mediated disease. The current inventionprovides a process for the preparation of a triazoles of formula 2 whichcan be transformed to the desired triazolones by process describedherein. The process comprises the condensation of 6 and the conjugatebase of 4 wherein Ar is phenyl substituted with 2 or 3 groupsindependently selected from halogen, cyano and C₁₋₆ haloalkyl, and R¹and R³ are C₁₋₁₀ alkyl, which process comprises the steps of:

(a) contacting 4 with a strong base in an inert solvent to form theconjugate base of 4 and contacting said conjugate base with 6 wherein Aris phenyl substituted with 2 or 3 groups independently selected fromhalogen, cyano and C₁₋₆ haloalkyl to afford 8;

(b) exposing 8 to conditions which result in hydrolysis of the ester anddecarboxylation of the resulting acid to afford 2.

The invention further comprises a process for replacing the nitro moietyof 2 with a chloro or bromo moiety and for further transforming thetriazole 14 to a triazolone 20 which process comprises the followingsteps:

(c) contacting 2 with a reducing agent capable of selective reduction ofthe nitro group to afford 12; and,

(d) contacting 12 with a diazotizing reagent and either Cu(I)Br/LiBr orCu(I)Cl/LiCl to afford 14 wherein R² is bromo and chloro respectively.

(e) exposing 14 to an oxidizing agent capable of selective oxidation ofthe sulfide to a sulfone 18; and

(f) contacting 18 with acetic acid/acetic anhydride under conditionswhich result in cleavage of the S-alkyl bond and hydrolysis of theresulting thiol to afford 20.

The present invention also provides new compounds of formula 4 whereinR¹ and R³ are independently C₁₋₁₀ alkyl which are useful for thepreparation of triazoles of formula 2 and triazolones of formula 20.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts the process for the preparation of3-aryloxy-2-fluoro-1-(4-methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-ylmethyl)phenylderivatives 2 and5-(4-halo-2-fluoro-3-aryloxy-benzyl)-4-methyl-2,4-dihydro-[1,2,4]triazol-3-onederivatives 20.

FIG. 2 depicts the process for the preparation of3-difluoromethyl-5-(2,3-difluoro-6-nitro-phenoxy)-benzonitrile (38) and(4-methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-acetic acidtert-butyl ester 4 (R¹ and R³=methyl)

DETAILED DESCRIPTION OF THE INVENTION

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other embodiments provided below, substituentswhich can be present in each embodiment and which are not explicitlydefined retain the broadest definition provided in the Summary of theInvention.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate a hydrogen or a substituent.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of a compoundor composition, the term “comprising” means that the compound orcomposition includes at least the recited features or components, butmay also include additional features or components.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

As used herein, the recitation of a numerical range for a variable isintended to convey that the invention may be practiced with the variableequal to any of the values within that range. Thus, for a variable whichis inherently discrete, the variable can be equal to any integer valueof the numerical range, including the end-points of the range.Similarly, for a variable which is inherently continuous, the variablecan be equal to any real value of the numerical range, including theend-points of the range. As an example, a variable which is described ashaving values between 0 and 2, can be 0, 1 or 2 for variables which areinherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other realvalue for variables which are inherently continuous.

A “stable” compound is a compound which can be prepared and isolated andwhose structure and properties remain or can be made to remainessentially unchanged for a period of time sufficient to allow the useof the compound for the purposes described herein (e.g., therapeutic orprophylactic administration to a subject).

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocyclic ring described as containing “1to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4 heteroatoms.It is also to be understood that any range cited herein includes withinits scope all of the subranges within that range. Thus, for example, anaryl or a heteroaryl described as optionally substituted with “from 1 to5 substituents” is intended to include as aspects thereof, any aryloptionally substituted with 1 to 4 substituents, 1 to 3 substituents, 1to 2 substituents, 2 to 5 substituents, 2 to 4 substituents, 2 to 3substituents, 3 to 5 substituents, 3 to 4 substituents, 4 to 5substituents, 1 substituent, 2 substituents, 3 substituents, 4substituents, and 5 substituents.

The symbols “*” at the end of a bond or

drawn through a bond each refer to the point of attachment of afunctional group or other chemical moiety to the rest of the molecule ofwhich it is a part. Thus, for example:

The term “inert organic solvent” or “inert solvent” as used herein meansthe solvent is inert under the conditions of the reaction beingdescribed in conjunction therewith, including for example, benzene,toluene, MeCN, THF, N,N-dimethylformamide, chloroform, DCM,dichloroethane, diethyl ether, EtOAc, acetone, methyl ethyl ketone,MeOH, EtOH, propanol, IPA, tert-butanol, dioxane, pyridine, and thelike. Unless specified to the contrary, the solvents used in thereactions of the present invention are inert solvents. Inert solventscompatible with strong bases do not have acidic protons which aresubject to abstraction and typically include aliphatic and arylhydrocarbons, ethers such as THF, DME, diethyl ether and dioxane orpolar aprotic solvents such as DMF, NMP and DMSO.

The term “strong base” as used herein refers to a basic compound ofsufficient basicity to abstract a proton from the methylene carbonbetween the ester moiety and the triazole ring of formula 4. Typicalbases which can be used include, but are not limited to, lithium dialkylamides such as lithium diisopropylamide, lithium dicyclohexylamide,potassium or sodium tert-butoxide, lithium or sodiumhexamethyldisilazane, and sodium or potassium hydride.

Selective hydrolysis of tert-butyl esters can be accomplished underacidic conditions such as TFA or HCl in ethereal solvents.

The term “diazotizing reagent” refers a reagent capable of converting anaryl amine to an aryl diazonium salt (e.g., Ph-N≡N⁺X⁻). Common reagentsto convert an aromatic amine to a diazonium salt include nitrous acid(sodium nitrite in acid solution) or alkyl nitrite such as tert-butylnitrite.

Oxidation of a thiol to a sulfoxide or sulfone is typically facile andnumerous reagents are known which capable of carrying out thistransformation. Sulfur oxidations are commonly carried out with aqueoussolutions of hydrogen peroxide, NaIO₄, tert-butyl hypochlorite, acylnitrites, sodium perborate, potassium hydrogen persulfate and peracidssuch as peracetic acid and meta-chloroperbenzoic acid. Typically withabout one equivalent of oxidant the sulfone can be isolated. Exposure totwo or more equivalents results in oxidation to the sulfone. Any oxidantcan be utilized in the present process without departing from the spiritof the invention.

Reduction of the nitro group can be carried out with a variety ofwell-known reducing agents. For example an activated metal such asactivated iron, zinc or tin (produced for example by washing iron powderwith a dilute acid solution such as dilute hydrochloric acid). Thereduction can also be carried out under a hydrogen atmosphere in thepresence of an inert solvent in the presence of a metal effective tocatalyze hydrogenation reactions such as platinum or palladium. Otherreagents which have been used to reduce nitro compounds to aminesinclude AlH₃—AlCl₃, hydrazine and a catalyst, TiCl₃, Al—NiCl₂-THF,formic acid and Pd/C and sulfides such as NaHS, (NH₄)₂S or polysulfides(i.e. the Zinn reaction). Aromatic nitro groups have been reduced withNaBH₄ or BH₃ in the presence of catalysts such as NiCl₂ and CoCl₂. Thusfor example, reduction may be effected by heating the nitro group in thepresence of a sufficiently activated metal such as Fe and a solvent ordiluent such as H₂O and alcohol, for example MeOH or EtOH at atemperature in the range of 50 to 150° C., conveniently at about 70° C.(J. March, Advanced Organic Chemistry, John Wiley & Sons: New York,N.Y., 1992, p. 1216). All reducing conditions capable of selectivereduction of the nitro group in intermediates described herein are withthe scope of the invention.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

The term “halogen” or “halo” as used herein means fluorine, chlorine,bromine, or iodine.

The term “haloalkyl” as used herein denotes a unbranched or branchedchain alkyl group as defined above wherein 1, 2, 3 or more hydrogenatoms are substituted by a halogen. Examples are 1-fluoromethyl,1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl,trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl,1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl,2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl,3-bromopropyl or 2,2,2-trifluoroethyl.

In one embodiment of the present invention there is provided a processfor the preparation of a compound according to formula 2 which processcomprises the steps of (a) contacting 4 with a strong base in an inertsolvent said strong base capable of forming the conjugate base of 4 andcontacting said conjugate base with 6 to afford 8; and, (b) exposing 8to reaction conditions which capable of hydrolyzing the ester anddecarboxylating the resulting carboxylic acid 8a wherein Ar is phenylsubstituted with 2 or 3 groups independently selected from halogen,cyano and C₁₋₆ haloalkyl, and R¹ and R³ are C₁₋₁₀ alkyl.

a second embodiment of the present invention there is provided a processfor the preparation of a compound according to formula 2 which processcomprises the steps of (a) contacting 4 with a strong base in an inertsolvent said strong base capable of forming the conjugate base of 4 andcontacting said conjugate base with 6 to afford 8; and, (b) exposing 8to reaction conditions which capable of hydrolyzing the ester anddecarboxylating the resulting carboxylic acid 8a wherein Ar is3-chloro-5-cyano-phenyl, 3,5-dicyano-phenyl or3-cyano-5-difluoromethyl-phenyl, R¹ is methyl and R³ is tert-Bu.

In a third embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of (a) contacting 4 with a strong base in aninert solvent said strong base capable of forming the conjugate base of4 and contacting said conjugate base with 6 to afford 8; and, (b)exposing 8 to reaction conditions which capable of hydrolyzing the esterand decarboxylating the resulting carboxylic acid 8a wherein Ar is3-chloro-5-cyano-phenyl, 3,5-dicyano-phenyl or3-cyano-5-difluoromethyl-phenyl, R¹ is methyl and R³ is tert-Bu, saidstrong base is potassium tert-butoxide, said inert solvent is THF andsaid hydrolysis conditions comprise methanesulfonic acid in acetonitrileat reflux temperature.

In a fourth embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of (a) contacting 4 with a strong base in aninert solvent said strong base capable of forming the conjugate base of4 and contacting said conjugate base with 6 to afford 8; and, (b)exposing 8 to reaction conditions which capable of hydrolyzing the esterand decarboxylating the resulting carboxylic acid 8a wherein Ar is3-cyano-5-difluoromethyl-phenyl, R¹ is methyl and R³ is tert-Bu, saidstrong base is potassium tert-butoxide, said inert solvent is THF andsaid hydrolysis conditions comprise methanesulfonic acid in acetonitrileat reflux temperature.

In a fifth embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of (a) contacting 4 with a strong base in aninert solvent said strong base capable of forming the conjugate base of4 and contacting said conjugate base with 6 to afford 8; (b) exposing 8to reaction conditions which capable of hydrolyzing the ester anddecarboxylating the resulting carboxylic acid 8a; (c) contacting 2 witha reducing agent capable of selective reduction of the nitro group toafford 12; and, (d) contacting 12 with a diazotizing reagent and eitherCu(I)Br/LiBr or Cu(I)Cl/LiCl to afford 14 wherein R² is bromo and chlororespectively, Ar is phenyl substituted with 2 or 3 groups independentlyselected from halogen, cyano and C₁₋₆ haloalkyl and R¹ and R³ are C₁₋₁₀alkyl. One skilled in the art will appreciate that other chloride andbromide salts can be used in place of the lithium salts recited hereinwithout departing from the spirit of the invention.

In a sixth embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of (a) contacting 4 with a strong base in aninert solvent said strong base capable of forming the conjugate base of4 and contacting said conjugate base with 6 to afford 8; (b) exposing 8to reaction conditions which capable of hydrolyzing the ester anddecarboxylating the resulting carboxylic acid 8a, (c) contacting 2 witha reducing agent capable of selective reduction of the nitro group toafford 12; and, (d) contacting 12 with a diazotizing reagent andCu(I)Br/LiBr to afford 14 wherein R² is bromo, Ar is3-cyano-5-difluoromethyl-phenyl, R¹ is methyl, R³ is tert-butyl, saidstrong base is potassium tert-butoxide, said inert solvent is THF, saidhydrolysis conditions comprise methanesulfonic acid in acetonitrile atreflux temperature, said reducing agent is hydrogen, Pd/C and VO(acac)₂and said diazotizing reagent is tert-butyl nitrite.

In a seventh embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of (a) contacting 4 with a strong base in aninert solvent said strong base capable of forming the conjugate base of4 and contacting said conjugate base with 6 to afford 8; (b) exposing 8to reaction conditions which capable of hydrolyzing the ester anddecarboxylating the resulting carboxylic acid 8a, (c) contacting 2 witha reducing agent capable of selective reduction of the nitro group toafford 12; (d) contacting 12 with a diazotizing reagent and Cu(I)Br/LiBrto afford 14 wherein R² is bromo, Ar is 3-cyano-5-difluoromethyl-phenyl,R¹ is methyl, R³ is tert-butyl, said strong base is potassiumtert-butoxide, said inert solvent is THF, said hydrolysis conditionscomprise methanesulfonic acid in acetonitrile at reflux temperature,said reducing agent is hydrogen, Pd/C and VO(acac)₂, said diazotizingreagent is tert-butyl nitrite; and (e) converting 14 to the tosylatesalt and recrystallizing said salt.

In an eighth embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of (a) contacting 4 with a strong base in aninert solvent said strong base capable of forming the conjugate base of4 and contacting said conjugate base with 6 to afford 8; (b) exposing 8to reaction conditions which capable of hydrolyzing the ester anddecarboxylating the resulting carboxylic acid 8a; (c) contacting 2 witha reducing agent capable of selective reduction of the nitro group toafford 12; (d) contacting 12 with a diazotizing reagent and Cu(I)Br/LiBrto afford 14; (e) exposing 14 to an oxidizing agent capable of oxidationof the sulfide to a sulfone 18; and (f) contacting 18 with aceticacid/acetic anhydride under conditions which result in cleavage of theS-heteroaryl bond and hydrolysis of the resulting acetate to afford 20wherein R² is bromo, Ar is 3-cyano-5-difluoromethyl-phenyl, and R¹ ismethyl and R³ are tert-butyl.

In a ninth embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of (a) contacting 4 with a strong base in aninert solvent said strong base capable of forming the conjugate base of4 and contacting said conjugate base with 6 to afford 8, (b) exposing 8to reaction conditions which capable of hydrolyzing the ester anddecarboxylating the resulting carboxylic acid 8a, (c) contacting 2 witha reducing agent capable of selective reduction of the nitro group toafford 12; (d) contacting 12 with a diazotizing reagent and eitherCu(I)Br/LiBr to afford 14, (e) exposing 14 to an oxidizing agent capableof oxidation of the sulfide to a sulfone 18; and (f) contacting 18 withacetic acid/acetic anhydride under conditions which result in cleavageof the S-heteroaryl bond and hydrolysis of the resulting acetate toafford 20 wherein R² is bromo; wherein Ar is3-cyano-5-difluoromethyl-phenyl, R¹ is methyl, R³ is tert-butyl, saidstrong base is potassium tert-butoxide, said inert solvent is THF, saidhydrolysis conditions comprise methane sulfonic acid in acetonitrile atreflux temperature said reducing agent is hydrogen, Pd/C and VO(acac)₂,said diazotizing reagent is tert-butyl nitrite, and said oxidizing agentis MCBPA.

In a tenth embodiment of the present invention there is provided acompound according to formula 4 wherein R¹ and R³ are independentlyC₁₋₁₀ alkyl.

In an eleventh embodiment of the present invention there is provided acompound according to formula 4 wherein R¹ is methyl and R³ istert-butyl.

In a twelfth embodiment of the present invention there is provided aprocess for preparing a compound according to formula 4 said processcomprising the steps of (a) contacting a half ester of malonic acid withCDI in an inert solvent to form a 3-imidazol-1-yl-3-oxo-propionic acidester (21), (b) contacting the resulting acylimidazole from step (a)with the thiosemicarbazide 22; and (c) treating the resulting5-thioxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylate 24 with analkylating agent to afford 4 wherein R¹ and R³ are C₁₋₁₀.

In a thirteenth embodiment of the present invention there is provided aprocess for preparing a compound according to formula 4 said processcomprising the steps of (a) contacting a half ester of malonic acid withCDI in an inert solvent to form a 3-imidazol-1-yl-3-oxo-propionic acidester (21), (b) contacting the resulting acylimidazole from step (a)with the thiosemicarbazide 22; and (c) treating the resulting5-thioxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylate 24 with analkylating agent to afford 4 wherein R¹ is Me and R³ is tert-Bu, saidhalf ester of malonic acid is tert-butyl hydrogen malonate and saidalkylating agent is methyl iodide.

In a fourteenth embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of: (a) contacting3,5-dibromo-fluoro-benzene (25) with iso-propyl magnesium chloride toafford a 3-bromo-5-fluoro-phenylmagnesium halide (26); (b) contacting 26with DMF followed by aqueous acid and MTBE to afford3-bromo-5-fluoro-benzaldehyde (28); (c) contacting 28 with DEOXO-FLUORand DCM to a afford 3-fluoro-5-difluoromethyl-1-bromo-benzene (30); (d)contacting 30 with p-methoxy-benzyl alcohol and potassium tert-butoxidein THF to afford1-bromo-3-difluoromethyl-5-(4-methoxy-benzyloxy)-benzene (32); (e)contacting a solution of 32 and NMP with potassium ferrocyanide, Na₂CO₃,Pd(OAc)₂ and DPPF at about 130° C. to afford 34; (f) treating a solutionof 34 and anisole with TFA at temperatures sufficient to cleave theO-benzyl linkage and afford 36; (g) treating a solution of 36 and THFwith 1,2,3-trifluoro-4-nitrobenzene (37) and K₂CO₃ to afford3-difluoromethyl-5-(2,3-difluoro-6-nitro-phenoxy)-benzonitrile (38); (h)contacting 4 with a strong base in an inert solvent said strong basecapable of forming the conjugate base of 4 and contacting said conjugatebase with 6 to afford 8; (i) exposing 8 to reaction conditions which arecapable of hydrolyzing the ester and decarboxylating the resultingcarboxylic acid 8a, (j) contacting 2 with a reducing agent capable ofselective reduction of the nitro group to afford 12; (k) contacting 12with a diazotizing reagent and either Cu(I)Br/LiBr or Cu(I)Cl/LiCl toafford 14, (l) exposing 14 to an oxidizing agent capable of oxidation ofthe sulfide to a sulfone 18; and (m) contacting 18 with aceticacid/acetic anhydride under conditions which result in cleavage of theS-heteroaryl bond and hydrolysis of the resulting acetate to afford 20wherein R² is bromo and chloro respectively, Ar is phenyl substitutedwith 2 or 3 groups independently selected from halogen, cyano and C₁₋₆haloalkyl, and R¹ and R³ are C₁₋₁₀ alkyl.

In a fifteenth embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula 2 whichprocess comprises the steps of: (a) contacting 25 with p-methoxy-benzylalcohol and potassium tert-butoxide in THF to afford 40; (b) contacting40 with iso-propyl magnesium chloride to afford 41;(b) contacting 41with DMF followed by aqueous acid and MTBE to afford 42; (d) contactinga solution of 42 and NMP with potassium ferrocyanide Na₂CO₃, Pd(OAc)₂and DPPF at 130° C. to afford 44; (e) treating a solution of 44 andanisole with TFA at temperatures sufficient to cleave the O-benzyllinkage and afford 46; (g) treating a solution of 46 and THF with1,2,3-trifluoro-4-nitrobenzene (37) and potassium carbonate to afford48; (h) contacting 48 with DEOXO-FLUOR and DCM to a afford 38; (g)contacting 4 with a strong base in an inert solvent said strong basecapable of forming the conjugate base of 4 and contacting said conjugatebase with 6 to afford 8; (h) exposing 8 to reaction conditions whichcapable of hydrolyzing the ester and decarboxylating the resultingcarboxylic acid 8a, (i) contacting 2 with a reducing agent capable ofselective reduction of the nitro group to afford 12; (j) contacting 12with a diazotizing reagent and either Cu(I)Br/LiBr or Cu(I)Cl/LiCl toafford 14, (k) exposing 14 to an oxidizing agent capable of oxidation ofthe sulfide to a sulfone 18; and (l) contacting 18 with aceticacid/acetic anhydride under conditions which result in cleavage of theS-heteroaryl bond and hydrolysis of the resulting acetate to afford 20wherein R² is bromo and chloro respectively, Ar is phenyl substitutedwith 2 or 3 groups independently selected from halogen, cyano and C₁₋₆haloalkyl, and R¹ and R³ are C₁₋₁₀ alkyl.

Commonly used abbreviations include: acetyl (Ac), atmospheres (Atm),tert-butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride(BOC₂O), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number(CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI),diethylaminosulfur trifluoride (DAST), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N,N′-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE),dichloromethane (DCM), diethyl azodicarboxylate (DEAD),bis-(2-methoxyethyl)amine sulfur trifluoride (DEOXO-FLUOR),di-iso-propylazodicarboxylate (DIAD), di-iso-butylaluminumhydride (DIBALor DIBAL-H), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide(DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), 1,1′-bis-(diphenylphosphino)ferrocene (DPPF),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), diethyl ether (Et₂O),acetic acid (HOAc), high pressure liquid chromatography (HPLC),iso-propanol (IPA), lithium hexamethyl disilazane (LiHMDS), methanol(MeOH), melting point (mp), MeSO₂— (mesyl or Ms), methyl (Me),acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum(ms), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS),N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone(NMP), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), pounds per squareinch (psi), pyridine (pyr), room temperature (rt or RT),tert-butyldimethylsilyl or t-BuMe₂Si (TBDMS), triethylamine (TEA orEt₃N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF₃SO₂—(TO, trifluoroacetic acid (TFA),1,1′-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), thin layerchromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me₃Si(TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C₆H₄SO₂—or tosyl (Ts), Conventional nomenclature including the prefixes normal(n), iso (i-), secondary (sec-), tertiary (tert-) and neo have theircustomary meaning when used with an alkyl moiety. (J. Rigaudy and D. P.Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press,Oxford.).

Process

5-Aralkyl-triazolones A-2 have been prepared by condensation of an acylhydrazide A-1b with methyl isocyanate to yield anN-acyl-N-carbamoylhydrazide A-1c which was cyclized to A-2 by treatmentwith methanolic potassium hydroxide.

While this sequence provided access to triazolone NNRTIs, experience soshowed that the reaction could be capricious and was not suitable forlarger scale synthesis. A new route which has proven general, convenientand amenable to large scale synthesis now has been identified.

The process provided herein comprises S_(N)Ar displacement of anaromatic fluoride with the enolate derived from an alkyl(4-alkyl-5-alkylsulfanyl-4H-[1,2,4]triazol-3-yl)-acetate. The resultingaralkyl ester is hydrolyzed and decarboxylated and the alkylthiotriazole converted to the desired triazolone under mild reactionconditions.

In U.S. Patent Publication 2005/0234236, published Oct. 20, 2005, D. J.Kertesz et al. disclose the arylation of alkyl(5-alkyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetates and dialkylmalonates with 2-aryloxy-3,4-difluoro-nitrobenzenes to afford6-benzyl-4-methyl-2H-pyridazin-3-one derivatives and 3-aryloxy-phenylacetic acid derivatives. The requisite2-aryloxy-3,4-difluoro-nitrobenzenes have been prepared by treating2,3,4-trifluoro-nitrobenzene with an appropriately substituted phenolresulting in the displacement of the 2-fluoro substituents with goodregioselectivity. An analogous sequence leading to3-aryloxy-phenylacetic acids has been described by J. P. Dunn et al. inU.S. Pat. No. 7,166,730 published Jan. 23, 2007.

Two routes for the preparation of3-difluoromethyl-5-(2,3-difluoro-6-nitro-phenoxy)-benzonitrile aredepicted in FIG. 2. Both routes commence with 3,5-dibromo-fluoro-benzene(25) utilizing similar reactions but the sequence of the reactionsdiffer. Route A begins by selective monometallation of 25 andformylation of the resulting aryl Grignard reagent. Fluorination ofaldehyde results in the introduction of the requisite difluoromethylsubstituent 30.

Aldehydes and ketones are converted an be converted into difluorocompounds with fluorinating reagents such as SF4/Lewis Acids, DAST(diethylaminosulfur trifluoride), bis-(2-methoxyethyl)aminosulfurtrifluoride in non-polar and non-basic solvent.

Aryl fluorides are generally significantly more labile than otherhalogen substituents. While hard nucleophiles like water and hydroxidefail to displace fluoride, soft nucleophiles like phenols, imidazoles,amines, thiols and some amides facilely displace fluorine at roomtemperature (D. Boger et al., Biorg. Med. Chem. Lett. 2000 10: 1471-75;F. Terrier Nucleophilic Aromatic Displacement: The Influence of theNitro Group VCH Publishers, New York, N.Y. 1991). Displacement of thefluoride with potassium salt of p-methoxy-benzyl alcohol affords aprotected phenol.

Palladium-mediated displacement of the bromo substituent with potassiumferrocyanide and Pd(OAc)₂ in the presence of DPPF afforded the requisitebenzonitrile 34 which could be deprotected by exposure to acid resultingin the expulsion of a p-methoxy-benzyl carbonium ion which is trappedwith anisole to afford 36.

The reaction of sodium methoxide with 2,3,4-trifluoronitrobenzene inmethanol has been reported to afford an inseparable mixture of thecorresponding 2- and 4-monomethoxy and 2,4-dimethoxy derivatives (P. M.O'Neill et al., J. Med. Chem. 1994 37:1362-70). Displacement of theortho-fluorine of 2,4-difluoronitrobenzene by amine nucleophiles alsohas been reported. (W. C. Lumma, Jr. et al., J. Med. Chem. 198124:93-101).

The reaction of 2,3,4-trifluoronitrobenzene (Aldrich catalog No. 33,836-2) with 3-difluoromethyl-5-hydroxy-benzonitrile resulted inregiospecific displacement of the 2-fluoro moiety to afford 38. Oneskilled in the art will immediately appreciate that although the processis exemplified with 36, a large number of substituted phenols orhydroxyl substituted heteroaromatic compounds are readily available andcould be used to afford many other anti-HIV-compounds.

The displacement reaction can be run in a variety of organic solventsincluding, but not limited to, ethers (e.g. diethyl ether, THF, DME anddioxane) and alcohols (e.g., iso-propanol and sec-butanol). Solventscapable of reacting with the fluoronitrobenzene are clearly precluded asare solvents which may result in the loss of regiochemical control. Thussecondary and tertiary alcohols are acceptable solvents but primaryalcohols can displace fluoride. The skilled chemist would be capable ofidentifying acceptable solvents with minimal experimentation. The phenolis treated with base to afford the phenolate salt. Any alkali metal saltcan be employed in the present process but the reaction is convenientlycarried out with the lithium, sodium or potassium salts. Sodiumphenolates are readily available by treating the phenol with sodiumtert-butoxide or sodium tert-amylate in tert-butanol or tert-amylalcohol respectively. The sodium alcoholate can be prepared by treatingthe alcohol with sodium metal or sodium hydride. Potassium phenolatescan be prepared analogously. Alternatively the phenol can be combinedwith the sodium alcoholate in THF to afford the salt. The reaction canbe run from about −30° C. to about 40° C. without significantdegradation of the regioselectivity. Typically the reactants arecombined at low temperature and allowed to warm to RT after an initialmixing. Under these conditions the aromatic nucleophilic displacementproceeds with high regioselectivity at the 2-position of the substrate.

The alternate route (FIG. 2, ROUTE B) proceeds by initially introducingthe PMB moiety which is sequentially formylated and treated withpotassium ferrocyanide and Pd(OAc)₂ in the presence of DPPF to afford44. Acid-catalyzed debenzylation and condensation with2,3,4-trifluoro-nitrobenzene affords 48. Finally fluorination of theformyl moiety with DEOXOFLUOR provides 36.

tert-Butyl (4-methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)acetate (4,R¹=methyl, R³=tert-butyl) was prepared by contacting tert-butyl hydrogenmalonate with carbonyl diimidazole to form the acylimidazole which isacylated with 4-methyl-3-thiosemicarbazide which subsequently undergoesintramolecular cyclization to afford 24 (FIG. 2). S-Alkylation proceedsrapidly when 24 is exposed to an alkylating agent. While methyl iodideis used in the example one skilled in the art will recognize that otherthioalkyl groups will function in a similar manner and exemplificationof the reaction scheme with a thiomethyl group should not presumed to belimiting. Similarly the reaction is exemplified with a tert-butyl ester,which is conveniently removed by acid treatment under mild conditions.Other esters, which may be more efficiently hydrolyzed under basicconditions, can be used without difficulty.

Contacting tert-butyl(4-methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-acetate withpotassium tert-butoxide and 36 resulted in the displacement of the4-fluoro substituent afforded 8 which was hydrolyzed with methanesulfonic acid. (FIG. 1) When the reaction was carried out at elevatedtemperatures the acid underwent concomitant decarboxylation to afford 2.Catalytic hydrogenation of the nitro group was carried out in thepresence of Pd on carbon and vanadium acetylacetonate which cleanlyafford the corresponding amine which could be converted thecorresponding bromo or chloro substituent by diazotizing the amine withtert-butyl nitrite in the presence of cuprous bromide and LiBr (orCuCl/LiCl to afford the corresponding chloride) which produced 14(R¹=Me, R²=Br and Ar=3-cyano-5-difluoromethyl-phenyl).

Finally elaboration of the triazolone ring was completed by oxidation ofthe thiomethyl to the sulfoxide. S-oxidation reactions can be performedusing a 30% aqueous solution of hydrogen peroxide, or by other oxidizingagents such as, NaIO₄, tert-butyloxychloride, acyl nitrites, sodiumperborate and peracids. Sulfides can be oxidized to sulfoxides which canbe further oxidized to sulfones by addition of another equivalent ofhydrogen peroxide, KMnO₄, sodium perborate, potassium hydrogenpersulfate, peracids or the like reagents. If enough oxidizing agent ispresent, sulfides can be converted directly to sulfones withoutisolation of the sulfoxides. Exposure of the sulfone to acetic anhydrideand acetic acid resulted in replacement of the methyl sulfone with anacetate and hydrolysis of the intermediate acetate to afford 20.

Example 1 3-Difluoromethyl-5-(2,3-difluoro-6-nitrophenoxy)benzonitrile(FIG. 2; ROUTE A)

step 1—To a solution of iso-propylmagnesium chloride in THF (500 mL of a2M solution in THF, 1.0 mol) and THF (200 mL) was added a solution of3,5-dibromofluorobenzene (25; 200 g, 0.79 mol) in THF (100 mL) whilemaintaining the temperature at ca. 0 C. After rinsing with THF (3×20 mL)the mixture was aged for 2 h at ca. 0° C. and then warmed to ca. 20° C.and aged for 0.5 h. The reaction was sampled by HPLC and then cooled toca. 0° C. DMF was added over 0.5 h while maintaining the temperature atca. 0° C. The mixture was aged 1.5 h at ca. 0° C. and then warmed slowlyto ca. 20° C. overnight. After sampling by HPLC, the mixture was dilutedwith heptane (200 mL) and then with a mixture of con HCl (120 mL)diluted to 360 mL with water. Con HCl (50 mL) was added to adjust the pHto <7. The organic phase was separated, washed with water (400 mL) andevaporated to dryness to afford 160.8 g (100.5%) of 28 as a yellow oilwhich solidified on standing.

step 2—To a solution of 28 (144.1 g, 0.71 mol) in THF cooled to ca. 0°C. was added and DEOXO-FLUOR® (bis-(2-methoxyethyl)amine sulfurtrifluoride; 218 mL, 261.6 g, 1.18 mol) in one portion. The mixture waswarmed to RT, aged for 3 h and the reaction monitored by HPLC. Theexcess reagent was quenched by transferring the reaction into saturatedNaHCO₃ (1200 mL). The organic phase was separated, washed with 1.5 N HCl(1000 mL), a mixture of water (250 mL) and saturated NaHCO₃ (250 mL),and finally with water (500 mL). The organic phase was concentrated toafford an oil which was fractionally distilled under vacuum to afford98.1 g (61.3%) of 30.

steps 3-5—p-Methoxybenzyl alcohol (36.8 g, 266.7 mmol) was added slowlyto a mixture of potassium t-butoxide (28.7 g, 255.5 mol) and THF (250mL). After stirring for about 15 min, 30 (50.0 g, 222.2 mmol) was addedand the reaction mixture heated to about 65° C. After stirring at 65° C.for 2 h, the reaction is analyzed by HPLC. After cooling to RT, amixture of saturated NaHCO₃ solution (150 mL) and water (150 mL) wasadded. Toluene (300 mL) was added, the organic phase separated andwashed with a mixture of saturated NaHCO₃ solution (75 mL) and water (75mL). Polish filtration and concentration in vacuo provided 83.9 g ofcrude 32 as an oil which is used without further purification.

To a solution of crude 32 in NMP (180 ml) was added potassiumferrocyanide (31.1 g, 84.44 mmol) and Na₂CO₃ (23.55 g, 222.2 mmol). Theresulting slurry was degassed thoroughly via repeated evacuation andpurging with nitrogen. The slurry was heated to about 100° C. and asolution of Pd(OAc)₂ (150 mg, 0.67 mmol) and DPPF (505 mg, 0.91 mmol) indegassed NMP (20 mL) added. The mixture was heated to ca. 130° C. forabout 3 h. HPLC analysis indicated ca. 5% starting material remained.Additional Pd(OAc)₂ (50 mg, 0.22 mmol) is added and heating at 130° C.was continued for 1.5 h when HPLC analysis showed complete conversion.

After cooling toluene (400 mL) and saturated sodium sulfite solution (10mL) are added and mixture heated at ca. 40° C. for about 1 h. Solka-floc(10 g) was added and the mixture was filtered through a bed ofSolka-floc and the cake was washed with toluene (ca. 100 mL total). Thefiltrate was washed successively with dilute sodium sulfite solution(1×400 mL) and water (2×200 mL). The combined aqueous phases areextracted with toluene (1×100 mL) and the toluene back extracted withwater (2×50 mL). The combined organic phases are polish filtered, andconcentrated in vacuo to obtain 70.4 g of 34 as a dark-colored oil (70.4g) which was used in the next step without further purification.

To the solution of crude 36 in toluene (190 mL) and anisole (65 mL) isadded TFA (25.3 g, 222.2 mmol). The reaction was heated to ca. 65° C.and stirred for about 2 h until the reaction was complete by HPLC. Themixture was distilled in vacuo to remove most of the TFA. After cooling,the mixture is extracted twice with ca. 10% Na₂CO₃ solution (300 mL then150 mL). The combined aqueous phases were acidified to a pH of 5.5 withon HCl and extracted with EtOAc (2×200 mL). The combined organic phaseswere washed with water (1×150 ml), polish filtered and the solventreplaced with toluene by vacuum distillation. The solution wasconcentrated to ca. 200 mL, then heptane (200 mL) was slowly added andthe mixture heated to 80° C. The mixture was cooled to RT, agedovernight, filtered, and washed with 50% heptane in toluene (ca. 30 mL).The isolated product was dried in vacuo at ca. 60° C. to afford 29.0 g(77.2% yield over 3 steps)of 36.

step 6—To a solution of 36 (0.80 g, 4.73 mmol) in THF (4.0 mL) was addedslowly via syringe pump (ca. 4.5 h) a mixture of 37 (0.57 mL, 0.88 g,4.97 mmol) and K₂CO₃ (1.96 g, 14.2 mmol) in THF (2.4 mL) at 0° C. Thereaction was aged at 0° C. until complete. Acetic acid (0.82 mL, 0.85 g,14.2 mmol) was added while maintaining the temperature at 5° C.,followed by water (4.0 mL), and the mixture as warmed to RT. After phaseseparation, the organic layer was washed with saturated NaCl (5 mL),concentrated, and the product purified by SiO₂ chromatography elutingwith 20% EtOAc/hexane to afford 1.24 g (80%) of 38 as an oil whichcrystallized on standing. An analytical sample obtained byrecrystallization from IPA/hexane.

Example 2 3-Difluoromethyl-5-(2,3-difluoro-6-nitrophenoxy)benzonitrile(FIG. 2; ROUTE B)

step 7—p-Methoxybenzyl alcohol (12.4 kg, 89.8 mol) was added slowly to amixture of potassium tert-butoxide (10.0 kg, 89.4 mol) in THF (78 L)allowing the reaction exotherm to raise the temperature to ca. 35° C.After stirring at 35 to 40° C. for 0.5 h, 25 (21.4 kg, 84.3 mol) wasadded slowly allowing the reaction to exotherm to reach ca. 60° C. Afterstirring at 60° C. for 2 h the reaction was monitored by hplc. Aftercooling to RT, HOAc (ca. 600 g) and then water (30 L) was added and thephases separated. The aqueous phase was extracted with EtOAc (20 L) andthe combined organic phases washed with a mixture of saturated brine (10kg) and water (10 L). The organic phase was concentrated in vacuo (ca.27 inches Hg, jacket temperature ca. 65° C.) to afford an oil. MeOH (ca.43 kg) was added to form a biphasic mixture which was aged at 45 to 50°C. The product precipitated and the slurry was stirred until a uniformconsistency was achieved. After cooling to RT, and aging overnight, theproduct was filtered off, washed with MeOH (9.8 kg), and dried undervacuum at 50° C. to afford 26.06 kg of 40. The material remaining in thereactor and filter was dissolved in THF (ca. 10 L) and the solutionevaporated to dryness on a rotary evaporator to afford an additional3.44 kg (94% overall)

step 8—To a solution of 40 (387 g, 1.04 mol) in THF (1.2 L) at RT wasadded iso-propyl magnesium chloride (0.7 L of a 2M solution in THF, 1.4mol) over ca. 15 min while maintaining the temperature between 20 and25° C. (mild exotherm). After aging 3 to 4 h the reaction was sampled toascertain whether the reaction was complete (HPLC). The mixture wascooled in a salt/ice bath (<−5° C.) and DMF (250 mL, 3.2 mol) added forseveral min (the addition is exothermic and should be controlled tomaintain the temperature at <30° C.). After aging 30 min, the mixturewas quenched by adding to a mixture of tert-butyl methyl ether (1 L) and1M H₂SO₄ (2 L). The organic phase was separated and washed withsaturated NaHCO₃ (1 L), water (1 L), dried (MgSO₄), filtered andevaporated to dryness. The product was dissolved in EtOAc (0.4 L) andheptane (0.8 L) and SiO₂ (340 g, 230-400 mesh) was added and stirred for2 h. The SiO₂ is filtered off, washed with a 33% EtOAc in heptane (0.6L) and evaporated to dryness to afford 345 g (107% yield) of 42.

step 9—To a solution of 42 (333 g, 1.037 mol) in NMP (1.7 L) was addedanhydrous powdered potassium ferrocyanide (115 g, 0.312 mol, dried at100° C. in vacuo, anhydrous Na₂CO₃ (110 g, 1.037 mol), Pd(OAc)₂ (0.23 g,0.001 mol) and DPPF (1.15 g, 0.002 mol). The flask was purged with atleast 3 vacuum/nitrogen cycles then heated to 130° C. until HPLCindicated the reaction was complete (3 to 6 h). The cooled reactionmixture was filtered through a CELITE® bed, TBME (4 L) was added, andthen the mixture washed with water (3×1 L). The organic phase isdecolorized with activated charcoal (25 g). After solvent exchange intoEtOAc (0.4 L) and hexanes (0.4 L), the mixture was cooled to ca. 0° C.The product was filtered, washed with 20% EtOAc/hexanes (2×0.2 L), anddried in vacuo at 60° C. overnight to afford 223 g (81%) of 44.

step 10—A mixture of 44 (201 g, 752 mmol), toluene (603 mL) and anisole(201 mL) was heated to ca. 50° C. TFA (90.0 g, 790 mmol) was added inone portion and the resulting mixture was heated to ca. 65° C. and agedfor about 1 h. The product may crystallize during the reaction which isassociated with ca. 10° C. exotherm. The reaction was monitored by HPLCand cooled to RT when complete. The product was filtered, washedsequentially with toluene (2×50 mL) and heptane (1×100 mL), dried invacuo at 70° C. to afford 106.1 g (95.9%) of 46.

step 11—A solution of 46 (95.0 g, 646 mmol) and THF (665 mL)was cooledto −10° C. and a solution of potassium tert-butoxide in THF (646 mL of a1M solution, 646 mmol) was added over 15 min. The resulting slurry wasmaintained at 0° C. for 45 min, cooled to −10° C. and then 37 (182.9 g,1.03 mol) was added rapidly. The slurry was warmed to 10° C. over 3 h atwhich point the mixture became homogeneous. The volume was reduced toone third in vacuo and then poured into cold water (2.4 L) with vigorousstirring. After stirring for 30 min, the solid was filtered, washed withwater (ca. 150 mL) and partially dried under vacuum at 45° C. The solidwas then triturated at 0° C. with enough Et₂O to form a stirrable slurry(ca. 150 mL). The slurry was filtered, washed with cold Et₂O (ca. 150 mLtotal), and then dried in vacuo at 45° C. to afford 141.4 g (72.0%) of48.

step 12—To a solution of 48 (140.0 g, 460 mmol) in DCM (1.4 L) was addedDEOXO-FLUOR® (203.6 g, 920 mmol) while maintaining the temperature atbetween 20 and 30° C. After aging overnight the mixture was quenched bydropwise addition of water (380 mL) while cooling with a −15° C. bath.The phases were separated and the organic phase was washed with water(380 mL) followed by saturated NaHCO₃ (2×380 mL). The DCM was evaporatedunder reduced pressure and the residue was taken up in IPA (700 mL) andfollowed by the addition of 25% sodium bisulfite solution (115 mL). Thiscloudy mixture was aged for 30 min at 45° C. and then approximately 70%of the IPA was replaced with water by distillation under reducedpressure. After stirring overnight, a mixture of crystals and hardenedchunks was isolated by filtration, crushed with a mortar and pestle, andthen washed in a filter with water (ca. 250 mL). After partial dryingunder vacuum at 50° C., the solid was triturated in a minimal amount ofcold Et₂O (ca. 80 mL; 0° C.), filtered, and washed with cold Et₂O (ca.50 mL). The product was dried in vacuo at 50° C. to afford 116.5 g(77.4%) of 38.

Example 3 (4-methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)acetic acidt-butyl ester

steps 1 & 2—To a solution of tert-butyl hydrogen malonate (93.7 g, 585mmol) in MeCN (1.6 L) was added 1,1′-carbonyldiimidazole (93.9 g, 579mmol) over 20 min at RT. After 1 h 4-methylthiosemicarbazide (92.3 g,878 mmol) was added over ca. 20 min. After stirring for 1 h, the slurrywas heated at reflux for 30 h and then cooled to RT. Concentration invacuo while replacing with water afforded a slurry. After aging at 0°C., the product was filtered off, washed with water, and dried in vacuoat 50° C. to afford 98.86 g (73.7%) of 24 which was recrystallized fromEtOAc.

step 3—A slurry of 24 (125.0 g, 550 mmol) in MeCN (600 mL) was treatedwith methyl iodide (93.7 g, 660 mmol). After stirring overnight thesolution was evaporated to afford a dark brown oil. The residue wasdissolved in DCM (250 mL) and washed sequentially with saturated NaHCO₃solution (75 mL), 25% sodium bisulfite solution (75 mL), water (75 mL),and saturated NaCl solution (75 mL). The organic phase was dried(Na₂SO₄), filtered and evaporated to afford 128.8 g (96.3%) of 4 (R¹=Meand R³=tert-Bu) as an oil that solidified on standing at RT.

Example 4

steps 1-3—To a solution of 6 (Ar=3-cyano-5-difluoromethyl-phenyl, 18.5g, 56.7 mmol) and 4 (16.55 g, 68.0 mmol) in THF (93 mL) was slowly addedpotassium t-butoxide (113.5 mL of a 1M solution in THF, 113.4 mmol)while maintaining the temperature between −20 to −10° C. The mixture waswarmed to 0° C., and HOAc (6.5 mL, 113.4 mmol) was added followed bywater (110 mL). After warming to RT the organic phase was separated.Most of the THF was evaporated in vacuo, MeCN (65 mL) was added and thesolution (ca. 70 mL) was filtered through a CELITE® pad. Methanesulfonicacid (11 mL, 170 mmol) was added and the solution was heated at refluxuntil the reaction was complete (ca. 4 h). After cooling, the mixturewas diluted sequentially with EtOAc (60 mL), water (60 mL) andsufficient saturated K₂CO₃ to adjust the pH to ca. 7. The aqueous phasewas separated, and extracted with EtOAc (20 mL). The combined organiclayers were filtered through a CELITE pad and Pd/C catalyst (JohnsonMatthey type A503023-5, 3.0 g) and vanadyl acetylacetonate (0.77 g, 2.8mmol) were added. The mixture was stirred under a hydrogen atmosphereuntil reduction of the nitro was complete. CELITE (5 g) was added andthen the mixture filtered through a CELITE pad (10 g) and the cakewashed with MeCN (5×20 mL). The filtrate was washed with a mixture ofsaturated NaCl (40 mL) and saturated NaHCO₃ (40 mL), followed bysaturated NaCl (30 mL). The organic phase was concentrated and theproduct crystallized from EtOAc (40 mL). Hexane (10 ml) was added to theslurry, which was cooled to 0° C. and aged for at least 2 h. The productwas filtered off, washed with 17% hexane in EtOAc (3×10 mL) and dried at55° C. in vacuo to afford 16.86 g (71% yield) of 12.

step 4—A mixture containing 12 (Ar=3-cyano-5-difluoromethyl-phenyl,41.45 g, 98.8 mmol), Cu(I)Br (57.86 g, 395 mmol), LiBr (26.54 g, 296mmol) and MeCN (620 mL) in an aluminum foil covered flask was heated to58° C. After 15 min, tert-butyl nitrite (20.04 mL, 198 mmol) was addedover 30 min while maintaining the temperature at ca. 58° C. After thereaction was complete, the mixture was concentrated to a minimum volume(ca. 600 mL solvent was collected). DCM (400 mL) was added followed by3M HCl (200 mL). The organic phase was separated and washed with 3M HCl(5×100 mL). After neutralization with aqueous K₂CO₃ to pH ca. 7, theorganic layer was washed with 6% sodium thiosulfate solution (690 g),saturated NaHCO₃ solution (250 mL), saturated NaCl solution (250 mL),and then filtered through a CELITE pad. p-Toluenesulfonic acid (21 g,108.7 mmol) was added and solvent was exchanged for EtOH (250 mL) byevaporation under reduced pressure. The volume of the slurry was reducedto ca. 125 mL by evaporation under reduced pressure. The slurry wascooled to RT and aged for at least 2 h. The product was filtered, thesolid washed with EtOH (2×50 mL), and dried at 65° C. in vacuo to afford43.0 g (66.4%) of 14 (R²=Br).

step 5—To a mixture of 14 (Ar=3-cyano-5-difluoromethyl-phenyl, R²=Br;25.0 g, 38 mmol), and HCO₂H (4.49 g, 114.4 mmol) in DCM (250 mL) wasadded 30% H₂O₂ (25.95 g, 228.8 mmol) over 5 min and the mixture heatedat reflux until the reaction was complete. The reaction was quenchedwith a solution of sodium sulfite (12.5 g, 99.1 mmol) in water (75 mL)and the pH adjusted to ca. 10 with 60% K₂CO₃ (ca. 25 mL). The aqueousphase was separated and extracted with DCM (2×100 mL). The combinedorganic extracts were washed with saturated NaCl (200 mL) and filteredthrough a CELITE pad. The solvent was exchanged for IPA and concentratedto ca. 200 mL. Hexane (50 mL) was added, and after crystals had formed,the mixture was aged at 60° C. for 2 h. The slurry was cooled to 25° C.and aged for 2 h. The product was filtered off, washed with 25% hexanein IPA (3×25 mL) and dried at 65° C. in vacuo to afford 17.7 g (90%) of18.

step 6—A mixture of 18 (Ar=3-cyano-5-difluoromethyl-phenyl, R²=Br; 9.29kg, 18.1 mol), Ac₂O (3.25 kg, 31.8 mol) and HOAc (36.0 kg) was heatedbetween 105 to 110° C. The mixture was aged for about h and monitored byHPLC. Upon completion, the mixture was cooled to ca. 35 to 45° C. andwater (7.5 L) was added. After aging at ca. 45° C. for 8 h, the reactionwas analyzed by HPLC. The mixture was cooled to between 15 to 25° C.,diluted with water (168 L) and then extracted with EtOAc (102 kg). Theorganic phase was washed sequentially with water (47 L), 10% NaHCO₃(2×77 L) and water (19 L). The organic phase was concentrated ca. 33 Lat atmospheric pressure and the mixture cooled to between 18 to 25° C.Once the crystallization began, heptane (3.9 kg) was slowly added. Aftercooling to 2° C., the product was filtered off, washed with a mixture of1:1 EtOAc and heptane and then dried in vacuo at between 50 and 60° C.to afford 6.12 kg (75%) of 20.

The features disclosed in the foregoing description, or the followingclaims, or the accompanying drawings, expressed in their specific formsor in terms of a means for performing the disclosed function, or amethod or process for attaining the disclosed result, as appropriate,may, separately, or in any combination of such features, be utilized forrealizing the invention in diverse forms thereof.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

1. A process for preparing a compound of formula 20 which processcomprises the steps of:

(a) exposing 14 to an oxidizing agent capable of oxidation of thesulfide to a sulfone 18; and (b) contacting 18 with acetic acid/aceticanhydride under conditions which result in cleavage of the S-alkyl bondand hydrolysis of the resulting thiol to afford 20.